Indoleacetic acid derivatives used as anti-inflammatories

ABSTRACT

1-(fluoro- or perfluoro lower alkyl-substituted benzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid carboxymethyl ester is found to have antiinflammatory and analgestic activity with less side effects on gastrointestinal traces than its homologue, acematacin or indometacin.

This is a continuation in part application of Application Ser. No.788,445 filed Oct. 17, 1985, now abandoned.

This invention relates to a novel indoleacetic acid derivative useful asan antiinflammatory and analgesic agent. More particularly, thisinvention relates to an indoleacetic acid derivative represented by thegeneral formula ##STR1## wherein R₁ is a fluorine atom or a perfluorolower alkyl group and m is an integer of 1 or 2.

Heretofore, an indoleacetic acid derivative having an inflammatory andanalgesic activity, such as1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid(so-called indometacin), has been made into a medical preparation fororal administration or as a suppository in its form of a free carboxylicacid and widely used clinically as such preparation. However, the use ofsuch preparations often causes serious side effects in gastrointestinaltracts, so that various derivatives have been proposed for the purposeof reducing the side effects. U.S. Pat. No. 3,845,210 to Sato et alclaims to comprise an analogous indoleacetic acid compound to theindometacin, in which 4-chlorobenzoyl moiety is replaced by4-fluorobenzoyl. However, no such compound is disclosed. An example ofsuch derivatives having a lower side effect is1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (called acemetacin) which is originally disclosed inU.S. Pat. Nos. 3,910,952, 4,104,278 and 4,459,415 to Bolze. However, thepurpose has not been fully attained up to the present.

An object of this invention is to provide an indoleacetic acidderivative having reduced side effects on gastrointestinal tracts andexcellent antiinflammatory and analgesic effects.

This invention relates to a novel indoleacetic acid derivativerepresented by the general formula (I).

In the general formula (I), R₁ is a fluorine atom or a lowerperfluoroalkyl group and may be present in a number of 1 or 2,preferably 1 as the substituent for the hydrogen atom(s) of the phenylgroup. The position of the phenyl group to which the substituent isattached may be any position, but p-position is preferable. The alkylmoiety in the lower perfluoroalkyl group is preferably those having 1 to3 carbon atoms, namely a perfluorinated methyl, ethyl, n-propyl orisopropyl group, and particularly preferably a perfluoro methyl group.

The indoleacetic acid derivative of the formula (I) can be prepared, forexample, by the following reaction schema: ##STR2##

In the above formulas, X represents a halogen (preferably chlorineatom), Y represents a halogen (preferably iodine atom) and R₁ and m arethe same as defined above.

The first step is the step of deriving the compound (III) from thecompound (II), and is conducted in the presence of n-butyllithium anddiisopropylamine. The reaction of this step is carried out under coolingat -60° to -85° C. for 20 to 50 minutes preferably in the presence of asolvent such as tetrahydrofuran.

The second step is the reaction of the compound (III) with the compound(IV) to give the compound (V). The reaction of this step is carried outat room temperature for 5 to 15 hours in a solvent, for example, onesimilar to that used in the first step.

The compound (V) thus produced can be purified and isolated from thereaction mixture according to a common procedure such as chromatographyand recrystalization, and undergoes the third step of which reaction isalready known.

The third step is the reaction of the compound (V) with the compound(VI) to give the compound (VII). This step is preferably conducted inthe presence of tetrabutylammonium hydrogen sulfate. The reaction ofthis step is carried out at room temperature for 1 to 3 hours preferablyin a solvent such as methylene chloride.

The fourth step is the step of deriving the compound (I) from thecompound (VII) by applying the conventional catalytic hydrogenationmethod. The reaction is carried out for 20 to 60 minutes in the presenceof a catalyst such as palladium/carbon in an inert solvent such as ethylacetate about at a room temperature under hydrogen atmosphere. Theindoleacetic acid derivative (I) thus formed can be isolated andpurified by conventional means such as solvent extraction,recrystallization and chromatography.

The indoleacetic acid derivative (I) or its pharmacologically acceptablesalt exhibits excellent antiinflammatory and analgesic effects and showsonly a very little gastroenteric trouble for mammals such as humans,horses, dogs, mice and rats. For example, in a suppression experimentagainst carrageenin edema using rats, the ED₄₀ of the Compound 1referred to later in Example 1, an indoleacetic acid derivative (I), is1.7 mg/kg p.o. as compared with 2.8 mg/kg p.o. of indometacin, thusshowing a higher suppression effect than that of indometacin. On theother hand, the gastric trouble caused by the Compound 1 is about onefourth of that by indometacin and the small-intestinal trouble is aboutone half of that caused by indometacin. As compared with acemetacin, theantiinflammatory effect of the Compound 1 is about three times and thegastroenteric trouble is one-half, respectively.

Thus, the indoleacetic acid derivative (I) shows an extremely excellentantiinflammatory and analgesic effect with very low side effects and isuseful as an inflammatory and analgesic agent.

The indoleacetic acid derivative (I) of this invention is used forantiinflammation and analgesia in admixture with conventional adjuvants.The administration thereof can be conducted by conventional methodsknown in the art including oral administration (in the form of tablets,capsules, granules and sirups); subcutaneous, intramuscular orintravenous injections; applications as known agents for external use;and rectal administration using suppositories. The does should be anamount sufficient for the antiinflammatory and analgesic effect to beexhibited and, though it may very depending, for examples, on theanimals to be treated, symptoms, administration routes and dosage forms,is 0.05 to 1 mg/kg, and preferably 0.1 to 0.3 mg/kg of body weight inone oral administration in general. The number of times ofadministration may be suitably selected according to the dose per day,the dosage schedule, the symptom, etc.

The indoleacetic acid derivative (I) of this invention can also be usedin combination with other antiinflammatory and analgesic agents.

The present invention is explained in detail by way of the followingExamples not limiting the invention.

(1) Synthesis of1-(4-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acid:

Dry isopropylamine, 4.5 ml (32 mmol), was dissolved in drytetrahydrofuran,50 ml, and the resulting solution was cooled to -78° C.Under nitrogen atmosphere, 20.6 ml of 1.55N n-butyllithium solution (32mmol) inhexane was added dropwise to the above solution with stirring,and the mixture was further stirred at -78° C. for 30 minutes. Then, asolution of 3.5 g (i6 mmol) of 5-methoxy-2-methyl-indole-3-acetic aciddissolved in 50 ml of dry tetrahydrofuran was added dropwise to theabove mixture at -78° C. with stirring. After completion of the dropwiseaddition, the resulting mixture was further stirred at -78° C. for 30minutes. Then, 3.33 g (20.8 mmol) of 4-fluorobenzoyl chloridedissolvedin 50 ml of dry tetrahydrofuran was added dropwise to thesolution with stirring at -78° C. After completion of the addition, theresultingreaction solution was gradually brought back to roomtemperature and further stirred overnight at the temperature. Thereaction mixture obtained was poured into 0.1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with water, thenwith saturated aqueous sodium chloride solution, and dried overanhydrous magnesium sulfate. After distilling off the solvent, theresidue was purified by silica gel column chromatography (using asolvent mixture of chloroform/methanol=26/1as the eluent) andrecrystallized from diethylether to give 2.9 g (yield: 52%) of thecompound mentioned in (1) above, melting at 143° to 144° C.

(2) Synthesis of1-(4-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidbenzyloxycarbonylmethyl ester:

To 8.5 ml of 1N aqueous sodium hydroxide solution, was added at 0° C.1.45 g (4.2 mmol) of tetrabutylammonium hydrogen sulfate and the mixturewas stirred. Then, 1.46 g (4.1 mmol) of the compound (I) obtained in thepreceding step was added thereto at room temperature and the mixture wasstirred. The resulting reaction solution was extracted with 30ml ofmethylene chloride, the extract was dried over anhydrous magnesiumsulfate and filtered, and the filtrate was cooled to 0° C. Then, asolution of 1.42 g (4.1 mmol) of benzyl iodoacetate in 4 ml of methylenechloride was added dropwise thereto with stirring. After completion ofthedropwise addition, the resulting mixture was stirred at 0° C. for30minutes and further at room temperature for 2.5 hours. Afterdistilling offthe solvent, the residue was purified by silica gel columnchromatography (using a solvent mixture of ethyl acetate/hexane=1/4 asthe eluent) to obtain 1.57 g (yield: 76%) of the compound (2) mentionedabove.

(3) Synthesis of1-(4-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester:

Into 80 ml of ethyl acetate, was dissolved 1.57 g (3.1 mmol) of thecompound (2) obtained in the preceding step, and 0.75 g of 10% palladiumon carbon powder was added thereto. The resulting solution was subjectedto hydrogenation with stirring for 30 minutes under hydrogen atmosphereatroom temperature. The palladium-carbon powder was removed byfiltration. Recrystallization from ethyl acetate-hexane gave 0.89 g(yield: 69%) of the compound mentioned in (3) above (hereinafterreferred to as "Compound 1"), melting at 144.5° to 145° C. The data on ¹HNMR and IR spectra of the Compound 1 are shown below.

¹ HNMR (CDCl₃ +DMSO-d₆): δ 7.91-6.50 (m, 7H), 4.56 (s,2H), 3.86-3.70(5H), 2.30 (s, 3H) IR (KBr, cm⁻¹): 3200-2600, 1730, 1670, 1600, 1210,850, 800

EXAMPLE 2

The Compounds 2 to 9 mentioned below were prepared in the same mannerusingthe raw materials in same molar amounts as in Example 1, providedthat in place of 4-fluorobenzoyl chloride various fluoro ortrifluoromethyl benzoyl chlorides were respectively used to obtain them.

1-(2-Fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 2)

m.p.: 172.5°-173° C. ¹ HNMR (CDCl₃ +DMSO-d₆): δ 9.11 (brs, 1H),7.70-6.52 (m, 7H), 4.56 (s, 2H), 3.80 (s, 3H), 3.74 (s, 2H), 2.28 (s,3H) IR (KBr, cm⁻¹): 3300-2700, 1740, 1710, 1670, 1615, 1155, 760

1-(3-Fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 3)

m.p.: 134°-136° C. ¹ HNMR (CDCl₃): δ 8.53 (s,1H), 7.59-6.53 (m, 7H),4.67 (s, 2H), 3.90-3.73 (5H), 2.35 (s, 3H) IR (KBr,cm⁻¹): 3550-3300,3100-2850, 1755, 1720, 1670, 1615, 1590, 1170, 795, 750

1-(2-Trifluoromethylbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 4)

m.p.: 121°-122° C. ¹ HNMR (CDCl₃): δ 9.58 (s,1H), 7.95-6.55 (m, 7H),4.65 (s, 2H), 3.79 (s, 3H), 3.73 (s, 2H), 2.20 (s, 3H) IR (KBr, cm⁻¹):3600-3300, 3000-2875, 1740, 1690, 1615, 1320, 1165, 770

1-(3-Trifluoromethylbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 5)

m.p.: 136°-138° C. ¹ HNMR (CDCl₃ +DMSO-d₆): δ 8.06-6.52 (m, 7H), 4.60(s, 2H), 3.93-3.68 (5H), 2.33 (s, 3H) IR (KBr, cm⁻¹): 3600-3300,3000-2875, 1755, 1740, 1690, 1615, 1310, 1165, 780

1-(4-Trifluoromethylbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 6)

m.p.: 166.5°-167° C. ¹ HNMR (CDCl₃ +DMSO-d₆): δ 7.81 (s, 4H), 7.12-6.51(m, 3H), 4.56 (s, 2H), 3.92-3.66 (5H), 2.22 (s, 3H) IR (KBr, cm⁻¹):3250-2800, 1750, 1735, 1680, 1615, 1605,1325, 1170, 855, 850, 800

1-(2,4-Difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 7)

m.p.: 156°-157° C. ¹ HNMR (CDCl₃ +DMSO-d₆): δ 7.76-5.87 (m), 4.56 (s,2H), 4.04-3.56 (5H), 2.27 (s, 3H) IR (KBr,cm⁻¹): 3300-2800, 1740, 1665,1610, 1230, 1150, 870, 800

1-(2,6-Difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 8)

m.p.: 185.5°-186.5° C. ¹ HNMR (CDCl₃ +DMSO-d₆): δ 9.40 (brs, 1H),7.76-6.58 (m, 6H), 4.55 (s, 2H), 3,80 (s, 3H), 3.72 (s, 2H), 2.24 (s,3H) IR (KBr, cm⁻¹): 3250-2800, 1750, 1720, 1680, 1630, 1170, 795

1-(3,4-Difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester (Compound 9)

m.p.: 128°-129° C. IR (KBr, cm⁻¹): 3100-2800, 1740, 1680, 1615, 1235,1160

Among the indoleacetic acid derivatives of the present invention,Compounds1 and 6 are most preferable.

EXPERIMENTAL EXAMPLE 1 (Antiinflammatory effect)

In one experimental test male rats of SD strain (in groups of 5) wereused.The animals were subcutaneously administered 0.1 ml of 1%carrageenin solution in physiological saline at the sole of their righthind legs to cause the onset of edema in their feet. The medicine to betested was orally administered to each individual in the group 30minutes before and 1 hour after the administration of carrageenin,respectively and the volume of the foot was measured at the time 3 hoursafter the carrageenin administration. The degree of suppression ofinflammation (edema suppresion) was determined in terms of thesuppression rate relative to the foot volume of the rat group which hadbeen given 0.5% CMC solution.

The experiments including contrast with administration of carrageeninonly were repeated 2 or 3 times with same or different amounts of themedicine for one group. The degree of suppression of inflammation(edema) is calculated by the following equation: ##EQU1##wherein E_(C)is an average edema volume increase rate after carrageeninadministration of the control group, and E_(S) is that after medicineadministration.

Based on the edema volume suppression rate (%) - dose (mg/kg),dose-responsive relationship is plotted in the semi-logarithumco-ordinatesystem in which doses are taken in logarithum on theabscissa, and edema suppression rate (%) is taken on the normalordinate. The method of least squares applies to the plotts to obtain aregression line. The dose responsive to edema suppression rate 40%(ED₄₀) is taken from the regression line in each of the repeated tests.The average value of all ofthe ED₄₀ 's with respect to the respectivemedicines is taken as the ED₄₀ thereof.

The edema suppression rate (%) obtained is shown in Table 1, and theED₄₀ calculated is in Table 2, with respect to the respective medicines.

                  TABLE 1                                                         ______________________________________                                                       Dose (mg/kg of                                                                animal weight)                                                                             Edema                                                            Each before and                                                                            Suppression                                                      after carrageenin                                                                          rate                                                       Tests administration                                                                             (%)                                               ______________________________________                                        Indomethacine                                                                            lst     0.3          15                                                               3            52                                            (Bolze:    2nd     0.3          26                                            U.S. Pat.          1            46                                            NO. 4,459,415)     3            58                                                       3rd     0.3          14                                                               3            49                                            Acemethacine                                                                             1st     1            31                                            (Bolze: ibid)      3            41                                                               10           56                                                       2nd     1            26                                                               3            48                                                               10           68                                            Sato et al 1st     0.3          9                                             compound           1            33                                            1-(4-fluoro-       3            32                                            benzoyl)-2-                                                                              2nd     0.3          10                                            5-methoxy          1            27                                            3-indolylacetic    3            49                                            acid                                                                          (not disclosed                                                                but falls into                                                                Sato et al                                                                    claim)                                                                        Compound 1 1st     0.1          15                                                               0.3          32                                            (Present           1            55                                            invention)         3            65                                                       2nd     0.3          25                                                               1            43                                                               3            46                                                       3rd     0.3          16                                                               1            37                                                               3            67                                            Compound 6 1st     1            0                                             (Present           3            32                                            invention)         10           63                                                       2nd     1            27                                                               3            40                                            ______________________________________                                    

                  TABLE 2                                                         ______________________________________                                                     ED.sub.40 (mg/kg)                                                             Tests                                                                         lst 2nd      3rd    Average                                      ______________________________________                                        Indomethacine  3.0   1.4      4.0  2.8                                        Acemethacine   4.8   4.6      --   4.7                                        Sato et al compound                                                                          6.0   3.4      --   4.7                                        Compound 1     1.0   2.0      2.0  1.7                                        Compound 6     8.0   6.0      --   7.0                                        ______________________________________                                    

EXPERIMENTAL EXAMPLE 2 (Side effect: Gastric trouble)

Male rats of SD strain (in groups of 7) were deprived of food for 24hours,then orally administered the medicine to be tested in amountsshown in Table 3, and further kept deprived of food and water for 5hours. Then, the animals were killed by carbon dioxide gas and thestomachs were exicsed from the animals with the lower part of theesophagus and the upper part of the duodenum attached thereto. They werefixed with 1% formaline, incised along the greater curvature of thestomach and examinedfor the state of hemorrhage and the state of ulcer.

In the examination, the ratings shown below were used as the ulcerindex.

0: No change

1: Hemorrhagic or inflamed state

2: 1 to 3 ulcers

3: 4 to 10 ulcers

4: 11 or more ulcers

The ulcer formation ratings responsive to doses were calculated andshown in Table 3.

                  TABLE 3                                                         ______________________________________                                                                Average ulcer                                                                 formation ratng                                                 Dose (mg/kg)  (n = 7)                                               ______________________________________                                        Indomethacine                                                                             3               2.1 ± 1.0                                                  6               3.4 ± 0.5                                                  10              4.0 ± 0                                        Acemethacine                                                                              3               0.9 ± 0.9                                                  10              3.0 ± 0.8                                                  30              3.9 ± 0.4                                      Sato et al  3               0.8 ± 0.6                                      compound    10              2.6 ± 0.5                                                  30              3.8 ± 0.4                                      Compound 1  3               0.6 ± 1.0                                                  10              2.0 ± 1.0                                                  30              3.7 ± 0.5                                      Compound 6  3               1.1 ± 0.9                                                  10              1.3 ± 0.8                                                  30              1.6 ± 0.8                                      ______________________________________                                    

Based on the ulcer formation in each dose, the least squares method wasapplied, and a curve was produced by taking dose on logarithm abscisaand ulcer index on normal ordinate with respect to each dose of themedicines.The curve was modified to obtain a regression line from whichdose responsive to ulcer formation rating 2 (UD₅₀) was obtained.

The result is shown in Table 4, in which the ratio of the UD₅₀ to ED₄₀(in Table 2) is given for demonstrating the therapeutic effect of eachmedicine. It will be noted that relatively, the larger the ratio, thesmaller the side effect is.

                  TABLE 4                                                         ______________________________________                                                    UD.sub.50 (mg/kg)                                                                       UD.sub.50 /ED.sub.40                                    ______________________________________                                        Indomethacine 2.7         0.94                                                Acemethacine  5.9         1.23                                                Sato et al    7.0         1.49                                                compound                                                                      Compound 1    9.4         5.54                                                Compound 6    150         21.42                                               ______________________________________                                    

EXPERIMENTAL EXAMPLE 3 (Side effect: Small-intestinal trouble)

Male rats of SD strain (in groups of 10) were orally administered themedicine to be tested and, after 3 days of normal breeding, killed bycarbon dioxide gas. The small-intestinal parts (duodenum, jejunum andileum) were excised from the animals, fixed with 1% formaline and thenincised to examine the state of ulcer and that of the adhesion ofintestinal tracts with the naked eye. When at least one ulcer wasobserved, the ulcer-forming effect was judged as positive. The positiverates responsive to doses were calculated and shown in Table 5. The UD₅₀values (the dose responsive to positive rate 50%) were calculatedaccording to the method of Litchfield & Wilcoxon and shown in Table 6together with the ratio of UD₅₀ to ED₄₀.

                  TABLE 5                                                         ______________________________________                                                       Dose     Positive rate                                         Drug.          (mg/kg)  (n = 10)                                              ______________________________________                                        Indometacin    3        0/10                                                                 6        1/10                                                                 8        8/10                                                                 10       10/10                                                 Acemetacin     3        0/10                                                                 6        3/10                                                                 10       9/10                                                                 30       10/10                                                 Compound 1     3        0/10                                                                 10       0/10                                                                 15       9/10                                                                 18       9/10                                                                 30       10/10                                                 Compound 6     3        0/10                                                                 10       1/10                                                                 30       8/10                                                  ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                    UD.sub.50 (mg/kg)                                                                       UD.sub.50 /ED.sub.40                                    ______________________________________                                        Indometacin   7           2.5                                                 Acemetacin    7           1.49                                                Compound 1    14          8.25                                                Compound 6    19          2.71                                                ______________________________________                                    

The indoleacetic acid derivative (I) may be formulated into an oraladministration preparation admixed with a conventional physiologicallyacceptable diluent, and can be orally administered to a mammal fortreating inflammation without the side effects in gastrointestinaltracks.

PREPARATION EXAMPLE 1

1-(4-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester . . . 20 mg

Magnesium stearate . . . 50 mg

Lactose . . . 50 mg

The ingredients listed above were composed to form a tablet eachweighing 120 mg.

What is claimed is:
 1. A process for treating inflammation in a mammalwhich comprises administrating to said mammal an effective amount of anidoleacetic acid derivative represented by the formula ##STR3## whereinR₁ is a fluorine atom or a C₁ -C₃ perfluoroalkyl group and m is aninteger of 1 or 2; and its pharmacologically acceptable salts.
 2. Theprocess of claim 1, wherein said mammal is administered an effectiveamount of the indoleacetic acid derivative represented by the formula##STR4## wherein R₁ is a fluorine atom or a trifluoromethyl group. 3.The process of claim 1, wherein said mammal is administered an effectiveamount of 1-(4-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 4. The process of claim 1, wherein said mammal isadministered an effective amount of1-(2-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 5. The process of claim 1, wherein said mammal isadministered an effective amount of1-(3-fluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 6. The process of claim 1, wherein said mammal isadministered an effective amount of1-(2,4-difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 7. The process of claim 1, wherein said mammal isadministered an effective amount of1-(2,6-difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 8. The process of claim 1, wherein said mammal isadministered an effective amount of1-(2-trifluoromethylbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 9. The process of claim 1, wherein said mammal isadministered an effective amount of1-(3-trifluoromethyl-benzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 10. The process of claim 1, wherein said mammal isadministered an effective amount of1-(4-trifluoromethylbenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.
 11. The process of claim 1, wherein said mammal isadministered an effective amount of1-(3,4-difluorobenzoyl)-5-methoxy-2-methyl-1H-indole-3-acetic acidcarboxymethyl ester.